Multiple sclerosis (MS) is commonly thought of as an inflammatory demyelinating disease of the CMS white matter. Yet, a growing body of evidence indicates a neurodegenerative component and that the gray matter is affected. Assessment of white matter volume and total parenchyma[unreadable] as a marker of neurodegeneration in MS is potentially contaminated by inflammatory activity and[unreadable] edema that raises the white matter volume. Because gray matter is less prone to fluctuations in[unreadable] volume due to the relative lack of inflammation and edema, gray matter volume may be a more[unreadable] pure, direct, and sensitive marker of neurodegeneration than either white matter volume or total[unreadable] brain volume. We will use magnetic resonance imaging (MRI) and a robust gray matter atrophy[unreadable] analysis method to determine the relationship between gray matter damage and the progressive[unreadable] neurologic and cognitive impairment and to characterize the rate of gray matter atrophy among[unreadable] phenotypes of MS in a three year longitudinal study. The automated atrophy segmentation[unreadable] method should allow a reliable and precise measurement of longitudinal gray matter atrophy. To[unreadable] assess the independent relationship between gray matter atrophy and clinical status, we will[unreadable] account for the influence of general conventional MRI lesion measures, white matter volume,[unreadable] total parenchyma! volume, diffuse occult disease (magnetization transfer ratio) in normal[unreadable] appearing brain tissue, and spinal cord atrophy. One potential benefit to the MS scientific field of[unreadable] this line of research is the emergence of automated gray matter volume measurement as a[unreadable] biologic marker/predictor of disease progression and a supportive outcome measure in[unreadable] therapeutic trials of putative neuroprotective agents. By establishing a longitudinal link between[unreadable] gray matter damage and progressive neurologic and cognitive dysfunction we also should gain a[unreadable] better understanding of the structural correlates of impairment.[unreadable]